Malaria is among the most significant public health problems in the world. The disease occurs in tropical and subtropical climates and affects over two million people annually while claiming nearly one million lives in 2009 (Wells et al., (2009) Nat. Rev. Drug Discovery 8: 879-891). P. falciparum and P. vivax are the two most prevalent species responsible for causing disease in humans. The development of curative antimalarial agents is difficult because of the various developmental stages of the parasite within the host. Following inoculation of sporozoites by an infected female Anopheles mosquito, the parasite must first undergo a proliferation period within the liver before the pathogenic infection of red blood cells ensues.
The most effective drug for liver stage infections is primaquine, an 8-aminoquinoline that acts on actively-growing liver stages and on the dormant forms known as hypnozoites that can lay dormant in a host for weeks to years and upon reactivation cause a relapse. Discovery and development of drugs active against hypnozoites are limited by the lack of reliable high or medium throughput assays. New drugs are, therefore, required that are safe and effective against liver and blood stage parasites simultaneously within the same host.
An additional difficulty for malaria drug development is the rapid emergence of multidrug resistance. Many of the common antimalarials such as atovaquone, chloroquine, and more recent artemisinin combination therapies (ACTs) have suffered from parasitological resistance being developed in many regions of the world, especially in Southeast Asia.
Advances in drug discovery such as high-throughput screening, physicochemical property assessment, synthetic methodologies, and improved in vivo efficacy protocols have allowed for re-examining old chemotypes or hits and for optimizing them to a more appropriate lead clinical candidate. Thus, endochin (1), a 4(1H)-quinolone, and its related tetrahydroacridone analogue (THA) floxacrine (2) were successfully optimized for antimalarial activity by substituting various benzenoid ring features and aryl moieties ((3) and (4)) while simultaneously assessing the physicochemical properties (FIG. 1).
Another such example is the 4(1H)-quinolone ester ICl 56,780 (5), which was found to have antimalarial activity (Ryley & Peters (1970) Ann. Trop. Med. Parasitol. 64: 209-222). This compound possesses blood schizontocidal activity against P. berghei and prophylactic activity against P. cynomolgi sporozoite challenge assays. It was shown that rhesus monkeys inoculated intravenously with P. cynomolgi sporozoites and subsequently treated for 5 to 7 consecutive days had no relapse after 120 days of exposure, confirming potency against hypnozoites. Compound (5) was found to be curative at 15 mg/kg. Unfortunately, rapid selection of resistance was obtained after one passage in P. berghei infected mice, leading to an abandonment of the compound.
The in vivo anti-relapse activity in combination with the excellent blood stage activity of (5) shows great promise in developing a viable multistage antimalarial agent. A related set of 4-oxo-3-carboxyl analogues (6) were recently developed by using a parallel approach of SAR and pharmacologic characterization to design quinolones that were less prone to cross-resistance with atovaquone.